1. Field of the Invention
The present invention relates to a method for predicting metastasis of an oral cavity cancer to a cervical lymph node and a diagnosis kit to be used in the prediction.
2. Description of the Related Art
An oral cavity cancer is a malignant tumor generated in an oral cavity. 90% and more of the oral cavity cancer is squamous epithelium carcinoma generated from oral mucosa. A surgery therapy and a radiation therapy are used as treatment for the oral cavity cancer. Hereby, relatively higher healing rates are expected. Actually, a region management ratio of the oral cavity cancer in Stage I and Stage II according to a UICC classification (Union International Contre Cancer) (in 2002) is in a range of 80% to 90%.
Metastasis to a cervical lymph node is cited to be an important prognostic factor to predict how the oral cavity cancer progresses after treatment.
The cervical lymph node plays a role of such a so called checkpoint of preventing cancer cells which flow in lymph from an oral cavity primary lesion from disseminating to a whole body. By capturing cancer cells, the cervical lymph node has a character that it swells at the position where the cancer cells are captured. In many cases, the swelling cervical lymph node is surgically extracted by an operation. Herein, it is suggested that the number of metastasis lymph nodes which are pathologically determined after surgery and whether or not cancer cells develop outside a membrane covering the lymph node are directly related to prognosis thereof.
Therefore, if the metastasis of the oral cavity cancer to the cervical lymph node for an oral cavity cancer patient is detected in early stages, improvement for the prognosis of the oral cavity cancer can be expected. For this reason, methods for predicting the metastasis to the cervical lymph node before treatment have been developed. Hereinafter, two conventional methods for predicting the metastasis of the oral cavity cancer to the cervical lymph node will be explained.
A first prediction method is a method of predicting metastasis by a clinical classification of cancers. For example, according to the clinical classification, tumor types of a lingual cancer included in the oral cavity cancer are classified into three types: superficial, outward, and inward types. Herein, it is known that an inward tumor metastasizes more easily than an outward tumor (for example, refer to Non Patent Documents 1 to 3, described below). That is, according to the first prediction method, a metastasis occurring rate to the cervical lymph node is estimated by the clinical classification of cancers.
A second prediction method is a method of predicting the metastasis by molecular pathological retrieving. Studies predicting metastasis for a case in which whether cancers metastasize or not is unknown, have been developed by analyzing a gene expression state of a cancer gene, a cancer-inhibiting gene, and genes related to a signaling factor and a cell adhesion. Recently it has become possible to exhaustively analyze a gene expression in a post-genome era. Studies using a microarray technology have been developed (for example, refer to Non-Patent Documents 4 to 8).
However, the first prediction method only shows a stochastically occurring rate on the metastasis to the cervical lymph node for a group of symptoms. Accordingly, there is a problem that the method does not predict the possibility of the metastasis to the cervical lymph node for an individual symptom.
Further, the second prediction method is expected to predict the possibility of the metastasis to the cervical lymph node for an individual symptom. However, the method has not been clinically applied to date.
More specifically, if a protein expression is determined by an immunogenic histological method, quantitative determination with reproducibility is difficult due to intrinsically subjective valuation property of the method, as described in Non-Patent Document 4.
Further, Non-Patent Document 5 describes analyses on relationships among a protein and mRNA expression of Cyclin D1 and a metastatic or prognostic progress; the relationships having been suggested heretofore, and the analyses are performed by using a FISH method having a high sensitivity for a gene amplification. According to the document, a high predicting rate that indicates a correct diagnosis rate of about 80% is achieved. However, it is suggested that the prediction method needs time and a labor cost because technique is required for the FISH method in itself and complicated processes are required to determine occurrence of a gene amplification (condition to determine presence of a CCND1 expression is that three and more signals are observed in 20% and more nuclei in 200 interphase cells). Accordingly, the complicated processes to the data determination together with the high costs required for the method may prevent the clinical application thereof.
Non-Patent Documents 6, 7 and 8 are articles in which a microarray technology is used.
According to Non-Patent Document 7, since the number of cases of a test group is only four, the number is too few for data to be authenticated sufficiently. Further, O'Donnell et al. perform a basic analysis on a comparison between a primary lesion and a metastatic lesion, and do not supply the clinical data on subjects. Therefore, it is difficult to apply their data to a clinical use.
According to Non-Patent Documents 6 and 8, Chung and Roepman et al. perform prophylactic cervical total dissection, chemotherapy and/or postoperative radiotherapy for treatment of a primary lesion. Although it is desirable to take a “wait and see policy” for a cervix to detect an occurrence of metastasis to a lymph node, the policy is not taken in the study. Further, a scoring method for the data is not defined clearly.
Therefore, it is desired to have a method for objectively predicting possibility of metastasis to a lymph node in an early stage for an individual case diagnosed as an oral cavity cancer.
[Non-Patent Document 1] Shibuya H., Hoshina M., Takeda M., Matsumoto S., Suzuki S., Okada N., “Brachytherapy for stage I and II oral tongue cancer: An analysis of past cases focusing on control and complications.” Int J Radiat Oncon Biol Phys 1993, 26, 51-8;
[Non-Patent Document 2] Nakagawa, T., Shibuya H., Yoshimura R., Miura M., Okada N., Kishimoto S., Amagasa M., Omura K., “Neck node metastasis after successful brachytherapy for early stage tongue carcinoma.” Radiotherapy and Oncology 2003, 68, 129-135;
[Non-Patent Document 3] the Scientific Committee of the Japan Society for Oral Tumor ed., Guideline for treatment of Lingual Cancers, Oral Tumor, 2005, 17 (1), 13-85.
[Non-Patent Document 4] Katayama A., Bandoh N., Kishibe K., Takahara M., Ogino T., Nonaka S., Harubuchi Y., “Expressions of matrix metalloproteinases in early-stage oral squamous cell carcinoma as predictive indicators for tumor metastases and prognosis.” Clinical Cancer Res 2004, 10, 634-640;
[Non-Patent Document 5] Myo K., Uzawa N., Miyamoto R., Sonoda I., Yuki Y., Amagasa T., “Cyclin D1 gene numerical aberration is a predictive marker for occult cervical lymph node metastasis in TNM stage I and II squamous cell carcinoma of the oral cavity.” Cancer 2005, 2709-2716;
[Non-Patent Document 6] Chung C., Parker J., Karaca G., Wu J., Funkhouser W., Moore D., Butterfoss D., Xiang D., Zanation A., Yin X., Shockley W., Weisser M., Dressler L., Shores C., Yarbrough W., Perou C., “Molecular classification of head and neck squamous cell carcinomas using patterns of gene expression.” Cancer Cell 2004, 5, 189-500;
[Non-Patent Document 7] O'Donnell R., Kupferman M., Wei S., Singhal S., Weber R., O'Malley B., Cheng Y., Putt M., Feidman M., Ziober B., Muschel R., “Gene expression signature predicts lymphatic metastasis in squamous cell carcinoma of the oral cavity.” Oncogene 2005, 24, 1244-1251;
[Non-Patent Document 8] Reopman P., Wessels F., Kettelarij N., Kemmeren P., Miles A., Lijnzaad P., Tilanus M., Koole R., HordijkG., Vliet P., Reinders M., Slootweg P., Holstege F., “An expression profile for diagnosis of lymph node metastases from primary head and neck squamous cell carcinomas.” Nature Genetics 2005, 37, 182-186.